AIM: To evaluate whether venlafaxine-extended release (VEN-XR) is an effective treatment for cannabis dependence with concurrent depressive disorders.DESIGN: This was a randomized, 12-week, double-blind, placebo-controlled trial of out-patients (n = 103) with DSM-IV cannabis dependence and major depressive disorder or dysthymia. Participants received up to 375 mg VEN-XR on a fixed-flexible schedule or placebo. All patients received weekly individual cognitive-behavioral psychotherapy that primarily targeted marijuana use.SETTINGS: The trial was conducted at two university research centers in the United States.PARTICIPANTS: One hundred and three cannabis-dependent adults participated in the trial.MEASUREMENTS: The primary outcome measures were (i) abstinence from marijuana defined as at least two consecutive urine-confirmed abstinent weeks and (ii) improvement in depressive symptoms based on the Hamilton Depression Rating Scale.FINDINGS: The proportion of patients achieving a clinically significant mood improvement (50% decrease in Hamilton Depression score from baseline) was high and did not differ between groups receiving VEN-XR (63%) and placebo (69%) (χ1 (2) = 0.48, P = 0.49). The proportion of patients achieving abstinence was low overall, but was significantly worse on VEN-XR (11.8%) compared to placebo (36.5%) (χ1 (2) = 7.46, P < 0.01; odds ratio = 4.51, 95% confidence interval: 1.53, 13.3). Mood improvement was associated with reduction in marijuana use in the placebo group (F1,179 = 30.49, P < 0.01), but not the VEN-XR group (F1,186 = 0.02, P = 0.89).CONCLUSIONS: For depressed, cannabis-dependent patients, venlafaxine-extended release does not appear to be effective at reducing depression and may lead to an increase in cannabis use.